* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Journal of Heterocyclic Chemistry, 1989, vol. 26, p. 257 - 264
2
[ 445-29-4 ]
[ 393-52-2 ]
Yield
Reaction Conditions
Operation in experiment
70%
With thionyl chloride In toluene at 50℃; for 7 h; Reflux
Step I 2-fluorobenzoyl chloride (Intermediate a) To 100mL of toluene were added 0.714 mol of 2-fluorobenzoic acid (100 g) then the mixture was heated to 50°C and added 5.7 mol (414mL) sulfoxide chloride .The reaction mixture was refluxed for 7 h. After completion of the reaction, sulfoxide chloride was evaporated to give 2-fluorobenzoyl chloride 79 g. Yield: 70percent.
70%
With thionyl chloride In toluene at 50℃; for 7 h;
To 100 mL of toluene were added 0.714 mol of 2-fluorobenzoic acid (100 g) then the mixture was heated to 50° C. and added 5.7 mol (414 mL) sulfoxide chloride. The reaction mixture was refluxed for 7 h. After completion of the reaction, sulfoxide chloride was evaporated to give 2-fluorobenzoyl chloride 79 g. Yield: 70percent.
Reference：
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[108] Patent: US4022900, 1977, A,
3
[ 445-29-4 ]
[ 393-52-2 ]
Reference：
[1] Patent: US4999356, 1991, A,
4
[ 445-29-4 ]
[ 393-52-2 ]
Reference：
[1] Patent: US4999356, 1991, A,
5
[ 445-29-4 ]
[ 393-52-2 ]
Reference：
[1] Patent: US4195023, 1980, A,
6
[ 10026-13-8 ]
[ 108-95-2 ]
[ 445-29-4 ]
[ 393-52-2 ]
Reference：
[1] Patent: US4999356, 1991, A,
7
[ 10026-13-8 ]
[ 108-95-2 ]
[ 445-29-4 ]
[ 393-52-2 ]
Reference：
[1] Patent: US4999356, 1991, A,
8
[ 3416-93-1 ]
[ 445-29-4 ]
[ 393-52-2 ]
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[1] Journal of the American Chemical Society, 2014, vol. 136, # 9, p. 3354 - 3357
9
[ 79-37-8 ]
[ 445-29-4 ]
[ 393-52-2 ]
Reference：
[1] Chemistry - A European Journal, 2017, vol. 23, # 50, p. 12149 - 12152
10
[ 445-29-4 ]
[ 7364-27-4 ]
Reference：
[1] Patent: WO2017/46318, 2017, A1,
11
[ 95-52-3 ]
[ 7726-95-6 ]
[ 446-48-0 ]
[ 446-51-5 ]
[ 446-52-6 ]
[ 445-29-4 ]
Reference：
[1] Journal of the Chemical Society, 1926, p. 220
12
[ 110-91-8 ]
[ 445-29-4 ]
[ 42106-48-9 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 18, p. 5134 - 5139
13
[ 445-29-4 ]
[ 7304-32-7 ]
Yield
Reaction Conditions
Operation in experiment
93%
at 10 - 25℃; for 2 h;
A35-a intermediate 36: 2-Fluoro- -nitrobenzoic acidNitric acid (60percent solution, 5.0 mL) was carefully added to a cooled solution of concentrate sulfuric acid (5.0 mL) so that the temperature did not exceed 10 °C. 2-f uorobenzoic acid (2.1 g, 15.0 mmol) was added by small portions while maintaining temperature between 15 and 25 °C. The mixture was stirred for 2 h at room temperature. Ice was added and the precipitate was filtered. After drying at room temperature, intermediate 36 was obtained as a white powder. Yield: 93percent; mp 135-137 °C; 1H NMR (300 MHz, OMSO-d6): δ = 7.32 (t, 1 H, H3, 3 J H3_H4 = J H3-F= 9.2 Hz), 8.43 (dt, 1 H, H JH4.H3 = 9.2 Hz, JH4.F = JH4.H6 = 3.5 Hz), 8.89 (dd, 1H, 3/4,4JH6.F = 5.8 Hz, 4JH6.H4 = 3.0 Hz); 13C NMR (75 MHz, DMSO- d6): δ = 118.7 (d, Ci, 2JC-F = 10.9 Hz), 118.7 (d, C3, 2JC-F = 25.0 Hz), 128.9 (d, C6>3JC-F = 2.2 Hz), 130.6 (d, C4,3JC- = 10.9 Hz), 143.9 (C5), 165.7 (d, C2, 1JC.F = 272.0 Hz), 166.7 (d, COOH, 3Jc- = 3.8 Hz).
Reference：
[1] Patent: WO2012/85003, 2012, A1, . Location in patent: Page/Page column 83
[2] Journal of Organic Chemistry, 2008, vol. 73, # 2, p. 538 - 549
[3] Journal of Heterocyclic Chemistry, 1998, vol. 35, # 6, p. 1301 - 1304
[4] Journal of Medicinal Chemistry, 2003, vol. 46, # 10, p. 1905 - 1917
[5] Australian Journal of Chemistry, 1981, vol. 34, # 5, p. 969 - 979
[6] Patent: US4565872, 1986, A,
[7] Patent: US4380543, 1983, A,
[8] Patent: US4400386, 1983, A,
14
[ 445-29-4 ]
[ 7304-32-7 ]
[ 317-46-4 ]
Reference：
[1] Bulletin des Societes Chimiques Belges, 1930, vol. 39, p. 101
[2] Recueil des Travaux Chimiques des Pays-Bas, 1914, vol. 33, p. 336
15
[ 445-29-4 ]
[ 2965-22-2 ]
Reference：
[1] Patent: WO2012/85003, 2012, A1,
16
[ 67-56-1 ]
[ 445-29-4 ]
[ 2965-22-2 ]
Reference：
[1] Journal of Organic Chemistry, 1990, vol. 55, # 7, p. 2034 - 2044
17
[ 445-29-4 ]
[ 348-52-7 ]
Yield
Reaction Conditions
Operation in experiment
64%
With N-iodo-succinimide; [4,4’-bis(tert-butyl)-2,2’-bipyridine]bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl]phenyl]iridium(III) hexafluorophosphate; iodine; caesium carbonate In 1,2-dichloro-ethane at 50℃; for 24 h; Inert atmosphere; Irradiation; Sealed tube
General procedure: To a 15 mL test tube with septum Cs2CO3 (0.6 mmol, 195 mg), aromaticcarboxylic acid (1) (0.3 mmol), [Ir(dF(CF3)ppy)2dtbbpy]PF6 (D) (6 μmmol, 6.7 mg), Niodosuccinimide(NIS) (0.9 mmol, 202.5 mg) and I2 (15 μmol, 5 molpercent) were added. The tube was evacuated and backfilled with argon for three times, and then 3 mL of dry 1,2-dichloroethane(DCE) was added through a syringer under argon. The tube was sealed with Parafilm M® andplaced in an oil bath with a contact thermometer, and the reaction was carried out at 50 °C underirradiation with 6 × 5 W blue LEDs (λmax = 455 nm). After 24 or 36 h, the resulting mixture wasfiltered through a 2 cm thick pad of silica, and the silica was washed with dichloromethane (DCM)(50 mL). The filtrate was collected and the solvent was removed in vacuo. The crude residue waspurified by silica gel flash column chromatography to provide the target product (2). (Note: Thereaction was very sensitive to moisture, and the yields sharply decreased to less than 5percent when0.01 equivalent of H2O was added to the reaction system).
Reference：
[1] European Journal of Medicinal Chemistry, 2017, vol. 138, p. 396 - 406
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[5] Journal of Agricultural and Food Chemistry, 2011, vol. 59, # 18, p. 9892 - 9900
[6] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 11, p. 3615 - 3621
[7] Medicinal Chemistry, 2012, vol. 8, # 6, p. 1190 - 1197,8
[8] Medicinal Chemistry, 2012, vol. 8, # 6, p. 1190 - 1197
[9] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 8, p. 2286 - 2297
[10] Journal of Heterocyclic Chemistry, 2013, vol. 50, # 4, p. 945 - 948
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[12] Chemical Biology and Drug Design, 2013, vol. 82, # 5, p. 546 - 556
[13] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 1, p. 192 - 194
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[15] Journal of Fluorescence, 2014, vol. 24, # 4, p. 995 - 1001
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[17] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 17, p. 6014 - 6024
[18] Transition Metal Chemistry, 2015, vol. 40, # 6, p. 665 - 671
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19
[ 64-17-5 ]
[ 445-29-4 ]
[ 443-26-5 ]
Reference：
[1] Journal of the American Chemical Society, 2017, vol. 139, # 23, p. 7745 - 7748
[2] Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 22, p. 7836 - 7841
[3] Journal of Agricultural and Food Chemistry, 2011, vol. 59, # 18, p. 9892 - 9900
[4] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 8, p. 2286 - 2297
[5] Journal of Heterocyclic Chemistry, 2013, vol. 50, # 4, p. 945 - 948
[6] Transition Metal Chemistry, 2015, vol. 40, # 6, p. 665 - 671
[7] Tetrahedron, 2014, vol. 70, # 12, p. 2190 - 2194
[8] Journal of Heterocyclic Chemistry, 2015, vol. 52, # 5, p. 1296 - 1301
[9] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 17, p. 6014 - 6024
[10] Chinese Chemical Letters, 2016, vol. 27, # 1, p. 163 - 167
[11] European Journal of Medicinal Chemistry, 2016, vol. 120, p. 134 - 147
[12] Journal of the Brazilian Chemical Society, 2016, vol. 27, # 11, p. 1998 - 2010
[13] Chemical Biology and Drug Design, 2017, vol. 90, # 2, p. 236 - 243
[14] RSC Advances, 2018, vol. 8, # 12, p. 6306 - 6314
20
[ 591-87-7 ]
[ 443-26-5 ]
[ 445-29-4 ]
Reference：
[1] Angewandte Chemie - International Edition, 2018, vol. 57, # 44, p. 14580 - 14584[2] Angew. Chem., 2018, vol. 130, p. 14788 - 14792,5
21
[ 446-52-6 ]
[ 445-28-3 ]
[ 445-29-4 ]
Yield
Reaction Conditions
Operation in experiment
24%
Stage #1: at -33℃; for 1 h; Inert atmosphere Stage #2: at -33℃; for 1 h; Inert atmosphere; Reflux
General procedure: Under an argon atmosphere, liquid NH3 (25 mL) was condensedin a two-neck round-bottom flask immersed in a dry ice coolingbath and equipped with a dry ice reflux condenser. Aldehyde(7.34 mmol) was added, and the resulting solution (or suspension)was stirred for 1 h. KMnO4 (7.34 mmol, 1.16 g) was added,the cooling bath was removed, and the reaction mixture wasstirred for another hour with gentle reflux of NH3. Na2SO3 (22.0mmol, 2.78 g) was added, the reflux condenser was removed,and the NH3 was allowed to evaporate spontaneously. The darkbrownresidue was treated with 6 M HCl (30 mL), and theresulting precipitate was filtered, washed with H2O (100 mL)and sat. aq NaHCO3 (20 mL). All products were recrystallizedfrom EtOH.
24%
Stage #1: at -33℃; for 1 h; Inert atmosphere Stage #2: for 1 h; Inert atmosphere; Reflux
General procedure: Under an argon atmosphere, liquid NH3 (25 mL) was condensedin a two-neck round-bottom flask immersed in a dry ice coolingbath and equipped with a dry ice reflux condenser. Aldehyde (7.34 mmol) was added, and the resulting solution (or suspension)was stirred for 1 h. KMnO4 (7.34 mmol, 1.16 g) was added,the cooling bath was removed, and the reaction mixture wasstirred for another hour with gentle reflux of NH3. Na2SO3 (22.0mmol, 2.78 g) was added, the reflux condenser was removed,and the NH3 was allowed to evaporate spontaneously. The darkbrownresidue was treated with 6 M HCl (30 mL), and theresulting precipitate was filtered, washed with H2O (100 mL)and sat. aq NaHCO3 (20 mL). All products were recrystallizedfrom EtOH.
Reference：
[1] Journal of Heterocyclic Chemistry, 1998, vol. 35, # 6, p. 1301 - 1304
28
[ 445-29-4 ]
[ 7304-32-7 ]
[ 317-46-4 ]
Reference：
[1] Bulletin des Societes Chimiques Belges, 1930, vol. 39, p. 101
[2] Recueil des Travaux Chimiques des Pays-Bas, 1914, vol. 33, p. 336
29
[ 445-29-4 ]
[ 111771-08-5 ]
Reference：
[1] Angewandte Chemie - International Edition, 2008, vol. 47, # 28, p. 5215 - 5219
[2] ACS Catalysis, 2018, vol. 8, # 2, p. 920 - 925
30
[ 445-29-4 ]
[ 146328-85-0 ]
Yield
Reaction Conditions
Operation in experiment
87.9%
With sodium periodate; sulfuric acid; sodium bromide In water; acetic acid at 30 - 65℃;
First, sodium periodate solution was configured: 7.7 g (36 mmol) of sodium periodate was dissolved in 40 ml of water and 26 ml of acetic acid.Next, add 10 g (71.4 mmol) of 2-fluorobenzoic acid, 7.35 g (71.4 mmol) of sodium bromide and sodium periodate solution to the reaction flask and heat to 30°C.At this temperature, 6.0 ml concentrated sulfuric acid was slowly added dropwise. After adding concentrated sulfuric acid, heat up to 50-65°C and react at this temperature for 2-3 hours.. Thin layer chromatography (TLC) detection reaction is completed, cooled, poured into ice water, solid precipitated, filtered,The filter cake was washed with water several times to obtain the product 2-chloro-5-bromobenzoic acid 14.6 g, yield 87.9percent.
77%
With potassium bromate; sulfuric acid In water at 90℃; for 2 h;
2-Fiuorobenzoic acid (1.0 g, 7.14 mmol), KBr03 (2.38 g, 14.28 mmol) and water (2 ml)were added to H2S04 (5 ml). This reaction mixture was stirred for 2 h at 90 °C. Theresulting mixture was extracted with ethyl acetate. The organic layer was dried over Na2S04, filtered and concentrated in vacuo to afford the crude product (1.2 g, 77 percent) as awhite solid.
Reference：
[1] Journal of Organometallic Chemistry, 2008, vol. 693, # 18, p. 3081 - 3091
[2] Patent: CN107954852, 2018, A, . Location in patent: Paragraph 0035-0037
[3] Patent: WO2017/46318, 2017, A1, . Location in patent: Page/Page column 54
31
[ 445-29-4 ]
[ 124700-41-0 ]
Reference：
[1] Journal of Medicinal Chemistry, 2006, vol. 49, # 5, p. 1506 - 1508
32
[ 445-29-4 ]
[ 37098-75-2 ]
Yield
Reaction Conditions
Operation in experiment
78.1%
With chlorosulfonic acid In water
(1a) 5-Chlorosulphonyl-2-fluorobenzoic acid (Compound VIA X=F) Commercially available 2-fluorobenzoic acid (75 g, 0.54 Mol) was added to chlorosulphonic acid (320 g) over 15 minutes, stirred for 30 minutes then heated to 90° C. for 41/2 hrs. Once cool, the reaction was quenched onto ice/water (1.5 kg/324 ml) and granulated for 1 hr. The precipitated product was filtered, water washed and dried at 50° C. under vacuo to give the title compound (99.7 g, 78.1percent) as a white solid.
73%
With chlorosulfonic acid In dichloromethane at 40℃; for 48 h;
2. Synthesis of Starting Material 21 or 21-1; The intensive trouble-shooting of the 4-step sequence from 2-fluorobenzoic acid (17) to 21 succeeded in an overall yield improvement from 17 to 50percent. The main enhancement was achieved by optimizing the reaction conditions to 19 with sodium sulfite followed by the alkylation reaction with R1hal (hal=I, Cl, Br) yielding 21 after saponification and crystallization. In a non-optimized reaction a one-pot procedure from 20 to 21-1 was demonstrated applying sodium sulfite in NaOH 32percent followed by the treatment of ClCH2CO2H yielding 21-1 in 61percent analogue to WO02/07238.
73%
at 0 - 75℃;
To a 500mL three-mouthed flask was added 50mL of chlorosulfonic acid and a stirred, and cooled to 0 deg. C, was added portionwise 18g 2-fluorobenzoic acid was slowly warmed to 75 deg. C, heated overnight, after which the reaction cooled to room temperature, with the stirring was poured into 400mL ice water, a large number of yellow solid was filtered, the cake washed with 30mL toluene and water 3 times. And dried in vacuo to give a yellow solid 22.6g. It was used directly in the next step, yield: 73percent.
72.2%
at 0 - 75℃; for 5 h;
416g of chlorosulfonic acid was added to a 1000ml reaction flask and cooled to below 0°C with iced saline.Stir and add 100g (0.71mol) of o-fluorobenzoic acid in portions; heat with oil bath, heat to 75°C, stir for 5 hours; cool to room temperature, drop the reaction into 300g ice, produce a white solid, filter, wash, Drying gave 123 g of a white solid, yield 72.2percent.
40.4%
at 0 - 75℃;
To chlorosulfonic acid (23.8 mL, 350 mmol) cooled to 0 °C was added portionwise 2-fluorobenzoic acid (5 g, 35 mmol). After complete addition, the yellow solution was allowed to warm to room temperature, then heated to 75 °C overnight. The reaction mixture was cooled to room temperature and then added dropwise to ice- water (150 mL). The white precipitate was filtered, washed with water, and dried in vacuo to afford the desired product B02 as a white solid (3.37 g, 40.4 percent).
10.5 g
at 0℃; for 1 h;
5-(N-((1-Cyclopropyl-1H-1,2,3-triazol-4-yl)methyl)sulfamoyl)-N-(3,4- difluorophenyl)-2-fluorobenzamide (13) 2-fluorobenzoic acid 9 (10.0 g, 71.4 mmol) was added to chlorosulfonic acid (50 mL) at 0 °C and the mixture was stirred at 0 °C for 1 h. The reaction mixture was then slowly poured onto ice. The precipitate formed was filtered, rinsed off with water (3 x 100 mL) and dried under vacuum overnight to yield 5-(chlorosulfonyl)-2- fluorobenzoic acid 10 as a brownish solid (10.5 g, 44.0 mmol). 5-(chlorosulfonyl)-2- fluorobenzoic acid 10 (10.0 g, 41.9 mmol) was added to 60 mL of SOCl2 at room temperature and the mixture was refluxed for 1.5 h. After removal of SOCl2 in vacuo, the residual oil was solubilized in toluene (150 mL) and 3,4-difluoroaniline (6.5 g, 50.3 mmol) was added. The mixture was stirred at 100 °C for 4 h and then cooled down to room temperature. The solution was then poured into a saturated solution of ammonium chloride (200 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by flash chromatography (Hexanes/EtOAc = 6:4 v/v) to yield 3- ((3,4-difluorophenyl)carbamoyl)-4-fluorobenzene-1-sulfonyl chloride 11 (92percent, 13.51 g, 38.6 mmol). To a solution of 3-((3,4-difluorophenyl)carbamoyl)-4-fluorobenzene-1- sulfonyl chloride 11 (10.0 g, 28.6 mmol) in CH2Cl2 (200 mL) at 0 °C were added propargylamine hydrochloride (3.1 g, 34.3 mmol) and Et3N (7.8 mL, 57.2 mmol). The reaction mixture was stirred overnight at room temperature and then poured into a saturated solution of ammonium chloride (250 mL). After extraction with CH2Cl2 (3 x 100 mL), the combined organic layers were dried over sodium sulfate and finally concentrated in vacuo. The resulting solid was washed with diethyl ether (50 mL) and hexanes (50 mL) to yield N-(3,4-difluorophenyl)-2-fluoro-5-(N-(prop-2-yn-1- yl)sulfamoyl)benzamide 12 (74percent, 7.8 g, 21.1 mmol) as a white powder. A solution of bromocyclopropane (0.6 mL, 4.9 mmol) and sodium azide (483 mg, 7.4 mmol) in water (1 mL) was heated under microwave irradiation for 30 minutes at 120 °C. To this solution were added a solution of compound 12 (0.1 g, 0.3 mmol) in acetonitrile (1 mL), sodium ascorbate (10 mg, 0.05 mmol) and copper sulfate (20 mg, 0.12 mmol). (0096) The reaction mixture was then heated for 30 minutes at 80 °C under microwave irradiation before being poured into a saturated solution of ammonium chloride (50 mL). After extraction with EtOAc (3 x 50 mL), the combined organic layers were dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by flash chromatography (Hexanes:EtOAc = 6:4 v/v) giving compound 13 as a white powder (19percent, 23 mg, 0.05 mmol). 1H NMR (400 MHz, Acetone-d6) δ 9.92 (s, 1H), 8.25 (dd, J = 6.6, 2.5 Hz, 1H), 8.06– 7.95 (m, 2H), 7.77 (s, 1H), 7.58– 7.52 (m, 1H), 7.48 (dd, J = 10.1, 8.7 Hz, 1H), 7.37 (dt, J = 10.6, 9.0 Hz, 1H), 7.21 (brs, 1H), 6.11– 5.94 (m, 1H), 5.32– 5.16 (m, 1H), 4.99 (dt, J = 6.0, 1.5 Hz, 2H), 4.32 (s, 2H). 13C NMR (101 MHz, Acetone-d6) δ 188.9, 167.9, 162.1, 150.2, 149.2 (d, J = 12.9 Hz), 146.8 (d, J = 13.0 Hz), 142.8, 137.9 (d, J = 5.9 Hz), 128.5, 124.6, 120.4– 118.2 (m), 117.5 (dd, J = 6.0, 3.6 Hz), 110.6 (d, J = 22.1 Hz), 81.5, 73.3, 33.2, 29.7, 12.8 (d, J = 9.6 Hz). 19F NMR (377 MHz, Acetone-d6) δ -110.6 (s), -139.6– - 139.7 (m), -146.1– -146.3 (m). HRMS (ESI): m/z [M+H]+ calcd for C19H17F3N5O3S: 452.1004, found: 452.0999.
Reference：
[1] Patent: US6207829, 2001, B1,
[2] European Journal of Medicinal Chemistry, 2017, vol. 138, p. 407 - 421
[3] Journal of Medicinal Chemistry, 2010, vol. 53, # 12, p. 4603 - 4614
[4] Patent: US2008/221327, 2008, A1, . Location in patent: Page/Page column 4-5
[5] Patent: CN105712952, 2016, A, . Location in patent: Paragraph 0346; 0347; 0348
[6] Patent: CN104628679, 2018, B, . Location in patent: Paragraph 0066-0068
[7] Patent: WO2013/96744, 2013, A1, . Location in patent: Page/Page column 224
[8] Patent: US3992441, 1976, A,
[9] Patent: US3992441, 1976, A,
[10] Patent: WO2008/70707, 2008, A1, . Location in patent: Page/Page column 22-23
[11] Angewandte Chemie - International Edition, 2017, vol. 56, # 1, p. 248 - 253[12] Angew. Chem., 2017, vol. 129, # 1, p. 254 - 259,6
[13] Patent: WO2017/156255, 2017, A1, . Location in patent: Page/Page column 84; 85
With tetrachloromethane; diethoxymethylsilane; Bis(p-nitrophenyl) phosphate; triphenylphosphine In toluene at 120℃; for 24 h; Reflux; Large scale
To the reactor was added o-fluorobenzoic acid (4,140 g, 1 mol), compound 3 (180 g, 1 mol), triphenylphosphine(52.4 g, 0.2 mol) carbon tetrachloride (152 g, 1 mol), diethoxymethylsilane (202.6 g, 1.2 mol)Bis (p-nitrophenyl) phosphate (17.1 g, 0.05 mol),500mL of toluene. 120 oil bath heated to reflux condensation reaction for 24 hours. Until the reaction liquid coldAfter that, it was extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by column chromatography to give the title compoundAtaluren (1,184.6 g) as a white solid in 65percent yield
Reference：
[1] Patent: CN106279057, 2017, A, . Location in patent: Paragraph 0023; 0024
36
[ 445-29-4 ]
[ 775304-57-9 ]
Reference：
[1] New Journal of Chemistry, 2014, vol. 38, # 7, p. 3062 - 3070
37
[ 6638-79-5 ]
[ 445-29-4 ]
[ 198967-24-7 ]
Yield
Reaction Conditions
Operation in experiment
73%
With N-ethyl-N,N-diisopropylamine; HATU In dichloromethane at 20℃; for 2 h;
2-Fluoro-N-methoxy-N-methylbenzamide was prepared in 73percent yield according to the Example 1 , Step A substituting 6-bromopicolinic acid for 2-fluorobenzoic acid.
Reference：
[1] Journal of the American Chemical Society, 2016, vol. 138, # 32, p. 10132 - 10135
39
[ 881676-32-0 ]
[ 445-29-4 ]
[ 881674-56-2 ]
Yield
Reaction Conditions
Operation in experiment
96.5%
With bis-triphenylphosphine-palladium(II) chloride; 1,10-Phenanthroline; copper (I) acetate; sodium hydroxide In dimethyl sulfoxide at 140℃; for 5 h; Inert atmosphere
Dimethyl sulfoxide (200 mL) was added to a 500 mL three-neck flask, and 2-fluorobenzoic acid (II) (14.2 g, 0.1 mol) was added under nitrogen.5-bromopyrrole-3-carbaldehyde (III) (35.5 g, 0.2 mol), sodium hydroxide (40.1 g, 1 mol), Pd(PPh3)2Cl2 (14.1 g, 0.02 mol), CuOAc (4.9 g, 0.04 mol) ,1,10-Phenanthroline (7.3g, 0.04mol), stirring, heating to 140°C, reaction for 5h,The reaction was completed by HPLC (2-fluorobenzoic acid (II) content is less than 1percent), the temperature was lowered to 20°C, the pH was adjusted to 6 with 5percent aqueous hydrochloric acid solution, and the solid was slowly precipitated by adding water.The solid was extracted with ethyl acetate (50 mL X 3).The resulting organic phase was washed with saturated sodium bicarbonate solution (100 mL) and saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to 80 g and re-crystallized by the dropwise addition of petroleum ether (150 mL).Filtration drying gave a reddish solid product (18.5 g, yield: 96.5percent based on 2-fluorobenzoic acid (II)).
Reference：
[1] Patent: CN107935902, 2018, A, . Location in patent: Paragraph 0044-0055
With carbon tetrabromide; oxygen; In acetonitrile; at 20℃; for 60h;UV-irradiation;
Add <strong>[95-52-3]2-fluorotoluene</strong> (55 mg, 0.5 mmol),Carbon tetrabromide (16mg, 0.05mmol) was addedInto a reaction flask filled with oxygen,Plug in an oxygen balloon,Finally add 10ml of acetonitrile,Reaction at 400nm LED wavelength and room temperature for 60h,After the reaction, the solvent was distilled off under reduced pressure.Add excess 2mol / L sodium hydroxide solution for washing,Adjust the pH to about 10 ~ 11,The aqueous phase was extracted multiple times with ethyl acetate,Then add 2mol / L of dilute hydrochloric acid to the water phase,Adjust the pH to 1-2,The aqueous phase was extracted again with ethyl acetate several times,Evaporate the ethyl acetate and dry,That gives compound 9,The yield was 41.4%.
With sulfuric acid; nitric acid; at 10 - 25℃; for 2h;
A35-a intermediate 36: 2-Fluoro- -nitrobenzoic acidNitric acid (60% solution, 5.0 mL) was carefully added to a cooled solution of concentrate sulfuric acid (5.0 mL) so that the temperature did not exceed 10 C. 2-f uorobenzoic acid (2.1 g, 15.0 mmol) was added by small portions while maintaining temperature between 15 and 25 C. The mixture was stirred for 2 h at room temperature. Ice was added and the precipitate was filtered. After drying at room temperature, intermediate 36 was obtained as a white powder. Yield: 93%; mp 135-137 C; 1H NMR (300 MHz, OMSO-d6): δ = 7.32 (t, 1 H, H3, 3 J H3_H4 = J H3-F = 9.2 Hz), 8.43 (dt, 1 H, H JH4.H3 = 9.2 Hz, JH4.F = JH4.H6 = 3.5 Hz), 8.89 (dd, 1H, ¾, 4JH6.F = 5.8 Hz, 4JH6.H4 = 3.0 Hz); 13C NMR (75 MHz, DMSO- d6): δ = 118.7 (d, Ci, 2JC-F = 10.9 Hz), 118.7 (d, C3, 2JC-F = 25.0 Hz), 128.9 (d, C6> 3JC-F = 2.2 Hz), 130.6 (d, C4, 3JC- = 10.9 Hz), 143.9 (C5), 165.7 (d, C2, 1JC.F = 272.0 Hz), 166.7 (d, COOH, 3Jc- = 3.8 Hz).
71.2%
With sulfuric acid; nitric acid; at 20℃; for 2h;
2-fluorobenzoic acid (5 g, 35.7 mmol) was dissolved in 11 mL of concentrated sulfuric acid.Slowly drip 11 mL of concentrated nitric acid in an ice bath and gradually increase to room temperature for 2 h.After the reaction was completed, the reaction solution was slowly dropped into ice water, and a large amount of white solid precipitated.Filtering and drying to obtain 4.7 g of 2-fluoro-5-nitrobenzoic acid, the yield is 71.2%;2-Fluoro-5-nitrobenzoic acid (500 mg, 2.7 mmol) was dissolved in 15 mL of dioxane.Add morpholine (1.2mL, 13.5mmol), react at room temperature for 2h, spin dry solvent and excess morpholine, dissolve in water, acidify with 10% dilute hydrochloric acid, and filter to give 2-morpholinyl-5-nitrobenzoic acid yellow 520 mg solid, 76.4% yield;2-morpholinyl-5-nitrobenzoic acid (80 mg, 0.32 mmol) was dissolved in 10 mL of DCM, and p-methoxybenzylamine (48 mg, 0.35 mmol), hydroxybenzotriazole (51 mg, 0.38 mmol) , EDCI (122 mg, 0.64 mmol), stirred at room temperature for 2 h, diluted with water, ethyl acetate (25 mL×3). : 1) A yellow solid 103 mg, a yield of 88.0%
71.2%
With sulfuric acid; nitric acid; at 0 - 20℃; for 2h;
To a solution of 2-fluorobenzoic acid (10) (5.0 g, 35.7 mmol) in10 mL concentrated H2SO4, 10 mL concentrated HNO3 was addeddropwise at 0 C. After stirring for 2 h at room temperature, themixture was slowly poured into ice water. The resulting precipitatewere collected by filtration, which werewashed bywater, and driedto give 4.7 g 2-fluoro-5-nitrobenzoic acid (11) as yellow solid, yield 71.2%; To the solution of 11 (500 mg, 2.7 mmol) in 10 mL dioxane,morpholine (1.2 mL, 13.5 mmol) was added in one potion. Afterstirring for 2 h at room temperature, the solvent and remainingmorpholine were removed in vacuo. Then, the residues were dissolvedinto water and neutralized by 10% HCl aqueous. Theresulting precipitate were collected, washed by water, and dried togive 520 mg 2- morpholine-5-nitrobenzoic acid (12) as yellowsolid, yield 76.4%. 1H NMR (300 MHz, DMSO-d6) d 8.40 (d, J 2.9 Hz,1H), 8.20 (dd, J 9.2, 2.9 Hz, 1H), 7.19 (d, J 9.2 Hz, 1H), 3.72 (d,J 4.8 Hz, 4H), 3.28 (d, J 4.7 Hz, 4H); 13C NMR (75 MHz, DMSO-d6)d 167.39, 155.09, 138.17, 127.42, 127.28, 120.86, 117.75, 65.70, 50.95;ESI-MS m/z 252.1 [M H]- 251.1.
54%
With sulfuric acid; nitric acid; at 15 - 25℃; for 1h;
To a mixture ofconc.sulfuricacid (10 mL) and conc.nitric acid (10 mL) was added 2-Fluorobenzoic acid (1.40 g,10 mmol).Thetemperature was maintained between 15-25C. The mixture was stirred for 1h after completion of theaddition,duringwhich time the temperature rose to 30C. The solution was decanted into 100 mL of ice water to provide 2-fluoro-4-nitrobenzoic acid (FBA) as a white solid (1.0 g, 54.0%).1H-NMR (400MHz,DMSO-d6,ppm):δ 8.594 (q,1H,J=3.2 Hz, 3.2 Hz, 2.8 Hz), 8.473 (m,1H,J=3.2 Hz, 0.8 Hz, 3.2 Hz, 2.0 Hz, 3.2 Hz, 0.8 Hz, 3.2 Hz), 7.610 (t,1H, 9.6 Hz, 9.6 Hz);13C-NMR (100MHz,DMSO-d6,ppm):δ 165.69, 163.16, 143.64, 129.80, 127.49, 120.42, 118.92; HRMS (ESI) m/zcalcdfor C7H4FNO4+H+: 186.01 [M+H]+;Found:186;m.p: 144-146C.
With sulfuric acid; nitric acid; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate;
Part A To a mixture of 225 ml (3.75 moles) of concentrated sulfuric acid and 225 ml (3.3 moles) of concentrated nitric acid was added 100 g (0.713 mole) of 2-fluorobenzoic acid. The temperature was maintained between 15 and 25 C. The mixture was stirred for an hour after completion of the addition, during which time the temperature rose to about 30 C. The solution was decanted into 4 liters of ice water to provide 111.1 g of white crystals of 2-fluoro-5-nitrobenzoic acid. The structural assignment was confirmed by infrared and nuclear magnetic resonance spectral analyses.
With sulfuric acid; nitric acid; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate;
Part A To a mixture of 225 ml (3.75 mole) of concentrated sulfuric acid and 225 ml (3.3 mole) of concentrated nitric acid was added 100 g (0.713 mole) of 2-fluorobenzoic acid. The temperature was maintained between 15 and 25 C. The mixture was stirred for an hour after completion of the addition. The temperature rose to about 30 C. The solution was decanted into 4 liters of ice water to provide 111.1 g of white crystals of 2-fluoro-5-nitrobenzoic acid. The structural assignment was confirmed by infrared and nuclear magnetic resonance spectral analyses.
With sulfuric acid; nitric acid; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate;
Part A To a mixture of 225 ml (3.75 mole) of concentrated sulfuric acid and 225 ml (3.3 mole) of concentrated nitric acid was added 100 g (0.713 mole) of 2-fluorobenzoic acid. The temperature was maintained between 15 and 25 C. The mixture was stirred for an hour after completion of the addition. The temperature rose to about 30 C. The solution was decanted into 4 liters of ice water to provide 111.1 g of white crystals of 2-fluoro-5-nitrobenzoic acid. The structural assignment was confirmed by infrared and nuclear magnetic resonance spectral analyses.
General procedure: In a 50 mL beaker, aldehyde (1 mmol) was roughly mixed with 1 g montmorillonite. After 2 min of mechanical stirring, DABCO (10 mmol) was added and then mixture was submitted into a single mode focused microwave reactor with continuous rotation for the time described in Table 1 (optimized time) at 40 C. After completing the reaction (TLC), water (30 mL) was added to the mixture ,the product was washed by CH2Cl2(2×10 mL), clay was filtered, and the solvent was evaporated to give the alcohol component. To obtain the acid component, the filtrate was acidified, extracted with CH2Cl2, and dried over magnesium sulphate. Then the solvent was evaporated to givethe acid component.The solid clay portion was washed with methanol and dried at 120 C under a reduced pressure to be reused in the subsequent reactions which showed the gradual decrease in the activity (Table 1). The filtrate was dried over MgSO4, the organic solvent was evaporated, and aryl alcohol was obtained. Isolated products were characterized by melting points, 1HNMR and 13C NMR spectrometric data and were compared with the literature and/or with authentic samples.
With sodium iodate; sulfuric acid; iodine; In dichloromethane; at 25 - 30℃; for 1h;
In a four-necked flask equipped with a thermometer and a stirrer, after dissolving 13.9 g of o-fluorobenzoic acid in 69.5 g of sulfuric acid and 55.6 g of DCM, 4.5 g of sodium iodate and 13.0 g of iodine were added to the reaction solution, and stirring was started to control the reaction. The temperature is 25-30 C, the reaction is kept for 1 h, and a purple solid is precipitated in the reaction liquid. After the reaction of the raw material is completed, the reaction solution is poured into a cold aqueous solution of sodium thiosulfate to be quenched, the reaction solution is spun and filtered, and 41.7 ml is used. Recrystallization of methanol gave 20 g of 2-fluoro-5-iodobenzoic acid. The yield was 75.8% and the purity was 99.0%.
With hydrogenchloride; PPA; aniline In ethanol; water
46.a a.
a. 4-Amino-2'-fluorobenzophenone To stirred 90° C. polyphosphoric acid (200 g) was added 14.29 g (10.2 mmol) of 2-fluorobenzoic acid and aniline (9.32 g 10.0 mmol) and the bath temperature raised to 180°-190° C. and held there for 1 hour. A solution was obtained at about 140° C. The heating bath was removed and the stirred mixture (sublimate above the solution) was treated cautiously with 80 mL of water. The mixture was stirred at 140°-155° C. for 1 hour, the heating bath removed, 66 mL of 3N HCl added, the mixture poured into 1 L of water and filtered through a pad of Celite. The filtrate was basified with 15% sodium hydroxide and the solid which formed on stirring was collected. The Celite pad was washed well with methylene chloride, the methylene chloride removed and the residue was combined with the solid obtained from basification of the aqueous phase. The combined material was dissolved in refluxing ethanol (175 mL), and treated hot with 125 mL of water. The brown solid obtaing on cooling was additionally recrystallized twice from ethyl acetate-hexane. Final purification by flash column chromatography (methylene chloride) yielded the aniline as a white solid (5.45 g, 25%); mp 128°-130° C. 1 H--NMR (250 MHz, d6 --DMSO): 6.32 (s, 2H, NH2) 6.60 (dd, 2H, J=8.6, 1.5 Hz, aromatic) 7.28-7.35 (m, 2H, aromatic) 7.40-7.60 (m, 4H, aromatic). MS (CI, CH4): 216 (M+1). Analysis for C13 H10 FNO: Calculated: C, 72.55; H, 4.68; N, 6.51. Found: C, 72.46; H, 4.82; N, 6.21.
A mixture of <strong>[13754-19-3]4,5-diaminopyrimidine</strong> (0.500 g), 2-fluorobenzoic acid (0.700 g) and polyphosphoric acid (25 mL) was heated at 180 C. for 3 hours. Then the reaction mixture was cooled and poured into water (500 mL). The solution was adjusted to pH=8-9 by addition of solid NaOH and the resulting precipitate was collected by filtration, washed with water and dried to give 8-(2-fluorophenyl)-purine (off-white powder, 88.5%). 1H NMR (200 MHz, DMSO-d6) delta 13.79 (br s, 1H, NH), 9.14 (s, 1H, purine-H), 8.95 (s, 1H, purine-H), 8.23 (m, 1H, phenyl-H), 7.73-7.41 (m, 3H, phenyl-H).
(1a) 5-Chlorosulphonyl-2-fluorobenzoic acid (Compound VIA X=F) Commercially available 2-fluorobenzoic acid (75 g, 0.54 Mol) was added to chlorosulphonic acid (320 g) over 15 minutes, stirred for 30 minutes then heated to 90 C. for 41/2 hrs. Once cool, the reaction was quenched onto ice/water (1.5 kg/324 ml) and granulated for 1 hr. The precipitated product was filtered, water washed and dried at 50 C. under vacuo to give the title compound (99.7 g, 78.1%) as a white solid.
77%
With chlorosulfonic acid;
To chlorosulfonic acid (23.8 mL, 0.35 mol, 10 equiv.) cooled to0 C was added portion wise 2-fluorobenzoic acid 1 (5.0 g,35 mmol). After addition, the yellow solution was allowed to warmto room temperature and heated at 75 C for 16 h. The reactionmixture was cooled to room temperature and carefully addeddropwise into crushed ice. The white precipitate was filtered,washed with water and dried in vacuo to afford compound 2 as awhite solid (6.4 g, 77%). Spectral data was consistent with thatpreviously reported. CAS: 37098-75-2.
73%
With chlorosulfonic acid; In dichloromethane; at 40℃; for 48h;
2. Synthesis of Starting Material 21 or 21-1; The intensive trouble-shooting of the 4-step sequence from 2-fluorobenzoic acid (17) to 21 succeeded in an overall yield improvement from 17 to 50%. The main enhancement was achieved by optimizing the reaction conditions to 19 with sodium sulfite followed by the alkylation reaction with R1hal (hal=I, Cl, Br) yielding 21 after saponification and crystallization. In a non-optimized reaction a one-pot procedure from 20 to 21-1 was demonstrated applying sodium sulfite in NaOH 32% followed by the treatment of ClCH2CO2H yielding 21-1 in 61% analogue to WO02/07238.
73%
With chlorosulfonic acid; at 0 - 75℃;
To a 500mL three-mouthed flask was added 50mL of chlorosulfonic acid and a stirred, and cooled to 0 deg. C, was added portionwise 18g 2-fluorobenzoic acid was slowly warmed to 75 deg. C, heated overnight, after which the reaction cooled to room temperature, with the stirring was poured into 400mL ice water, a large number of yellow solid was filtered, the cake washed with 30mL toluene and water 3 times. And dried in vacuo to give a yellow solid 22.6g. It was used directly in the next step, yield: 73%.
72.2%
With chlorosulfonic acid; at 0 - 75℃; for 5h;
416g of chlorosulfonic acid was added to a 1000ml reaction flask and cooled to below 0C with iced saline.Stir and add 100g (0.71mol) of o-fluorobenzoic acid in portions; heat with oil bath, heat to 75C, stir for 5 hours; cool to room temperature, drop the reaction into 300g ice, produce a white solid, filter, wash, Drying gave 123 g of a white solid, yield 72.2%.
40.4%
With chlorosulfonic acid; at 0 - 75℃;
To chlorosulfonic acid (23.8 mL, 350 mmol) cooled to 0 C was added portionwise 2-fluorobenzoic acid (5 g, 35 mmol). After complete addition, the yellow solution was allowed to warm to room temperature, then heated to 75 C overnight. The reaction mixture was cooled to room temperature and then added dropwise to ice- water (150 mL). The white precipitate was filtered, washed with water, and dried in vacuo to afford the desired product B02 as a white solid (3.37 g, 40.4 %).
EXAMPLE 14 Starting with o-fluorobenzoic acid and following the chlorosulfonation conditions of Example 1, 2-fluoro-5-chlorosulfonylbenzoic acid is prepared.
With chlorosulfonic acid;
EXAMPLE 15 2N,N-diethylamino-5-(3,5-dimethylpiperidinosulfonyl)benzoic Acid o-Fluorobenzoic acid is reacted with chlorosulfonic acid by the method of Example 1 to form 2-fluoro-5-chlorosulfonylbenzoic acid.
With chlorosulfonic acid; at 200℃; for 0.0541667h;microwave irradiation;
Example 1; Preparation of 5-[fethylamino)sulfonyll-2-fluoro-N-[5-fl-methyl-l- phenylethyl)- 1 ,3i4-thiadiazol-2-yll benzamide; Intermediate 1; 5-(Chlorosulfonyl)-2-fluorobenzoic acid (General procedure 1); 5-(Chlorosulfonyl)-2-fluorobenzoic acid was prepared from 2-fluorobenzoic acid using a Biotage Initiator 8 microwave set to high absorbance as follows. Using conditions described, the reaction typically reached a pressure of 12 barr. The pressure was reduced to 3 barr after cooling and was vented prior to decapping the reaction vessel. To a 5 ml Biotage microwave reaction tube was added 2- fluorobenzoic acid (0.5 g, 3.57mmol) and a Teflon covered magnetic stir-bar. To this was added 2 ml of chlorosulfuric acid. The vessel was capped and heated to 2000C for 3.25 min. After cooling to room temperature, the remaining pressure was vented into a 50 ml syringe and discharged into 30 ml IM NaOH. Reaction was quenched by adding dropwise to 30 ml of crushed ice. The solid product was <n="24"/>collected by vacuum filtration, washed with water (5ml, 3x) and air-dried under vacuum for 2 h, yielding 5-(chlorosulfonyl)-2-fluorobenzoic acid as a light yellow solid.MS (ESI): 238.9 [M+H]+.
10.5 g
With chlorosulfonic acid; at 0℃; for 1h;
5-(N-((1-Cyclopropyl-1H-1,2,3-triazol-4-yl)methyl)sulfamoyl)-N-(3,4- difluorophenyl)-2-fluorobenzamide (13) 2-fluorobenzoic acid 9 (10.0 g, 71.4 mmol) was added to chlorosulfonic acid (50 mL) at 0 C and the mixture was stirred at 0 C for 1 h. The reaction mixture was then slowly poured onto ice. The precipitate formed was filtered, rinsed off with water (3 x 100 mL) and dried under vacuum overnight to yield 5-(chlorosulfonyl)-2- fluorobenzoic acid 10 as a brownish solid (10.5 g, 44.0 mmol). 5-(chlorosulfonyl)-2- fluorobenzoic acid 10 (10.0 g, 41.9 mmol) was added to 60 mL of SOCl2 at room temperature and the mixture was refluxed for 1.5 h. After removal of SOCl2 in vacuo, the residual oil was solubilized in toluene (150 mL) and 3,4-difluoroaniline (6.5 g, 50.3 mmol) was added. The mixture was stirred at 100 C for 4 h and then cooled down to room temperature. The solution was then poured into a saturated solution of ammonium chloride (200 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by flash chromatography (Hexanes/EtOAc = 6:4 v/v) to yield 3- ((3,4-difluorophenyl)carbamoyl)-4-fluorobenzene-1-sulfonyl chloride 11 (92%, 13.51 g, 38.6 mmol). To a solution of 3-((3,4-difluorophenyl)carbamoyl)-4-fluorobenzene-1- sulfonyl chloride 11 (10.0 g, 28.6 mmol) in CH2Cl2 (200 mL) at 0 C were added propargylamine hydrochloride (3.1 g, 34.3 mmol) and Et3N (7.8 mL, 57.2 mmol). The reaction mixture was stirred overnight at room temperature and then poured into a saturated solution of ammonium chloride (250 mL). After extraction with CH2Cl2 (3 x 100 mL), the combined organic layers were dried over sodium sulfate and finally concentrated in vacuo. The resulting solid was washed with diethyl ether (50 mL) and hexanes (50 mL) to yield N-(3,4-difluorophenyl)-2-fluoro-5-(N-(prop-2-yn-1- yl)sulfamoyl)benzamide 12 (74%, 7.8 g, 21.1 mmol) as a white powder. A solution of bromocyclopropane (0.6 mL, 4.9 mmol) and sodium azide (483 mg, 7.4 mmol) in water (1 mL) was heated under microwave irradiation for 30 minutes at 120 C. To this solution were added a solution of compound 12 (0.1 g, 0.3 mmol) in acetonitrile (1 mL), sodium ascorbate (10 mg, 0.05 mmol) and copper sulfate (20 mg, 0.12 mmol). (0096) The reaction mixture was then heated for 30 minutes at 80 C under microwave irradiation before being poured into a saturated solution of ammonium chloride (50 mL). After extraction with EtOAc (3 x 50 mL), the combined organic layers were dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by flash chromatography (Hexanes:EtOAc = 6:4 v/v) giving compound 13 as a white powder (19%, 23 mg, 0.05 mmol). 1H NMR (400 MHz, Acetone-d6) delta 9.92 (s, 1H), 8.25 (dd, J = 6.6, 2.5 Hz, 1H), 8.06- 7.95 (m, 2H), 7.77 (s, 1H), 7.58- 7.52 (m, 1H), 7.48 (dd, J = 10.1, 8.7 Hz, 1H), 7.37 (dt, J = 10.6, 9.0 Hz, 1H), 7.21 (brs, 1H), 6.11- 5.94 (m, 1H), 5.32- 5.16 (m, 1H), 4.99 (dt, J = 6.0, 1.5 Hz, 2H), 4.32 (s, 2H). 13C NMR (101 MHz, Acetone-d6) delta 188.9, 167.9, 162.1, 150.2, 149.2 (d, J = 12.9 Hz), 146.8 (d, J = 13.0 Hz), 142.8, 137.9 (d, J = 5.9 Hz), 128.5, 124.6, 120.4- 118.2 (m), 117.5 (dd, J = 6.0, 3.6 Hz), 110.6 (d, J = 22.1 Hz), 81.5, 73.3, 33.2, 29.7, 12.8 (d, J = 9.6 Hz). 19F NMR (377 MHz, Acetone-d6) delta -110.6 (s), -139.6- - 139.7 (m), -146.1- -146.3 (m). HRMS (ESI): m/z [M+H]+ calcd for C19H17F3N5O3S: 452.1004, found: 452.0999.
General Procedure E for the Synthesis of Fluoroethyl Substituted Indan Ureas A mixture of SOCl2 (1.5 eq) and substituted benzoic acids in benzene was refluxed until no more gas evolution was observed. After cooling to room temperature the mixture was concentrated on a rotary evaporator. The concentrate was taken up in dichloroethane and added to a solution of AlCl3 (1.0 eq) in dichloroethane at 10-20 C. Ethylene was bubbled for 4 hours after which the resulting mixture was stirred overnight and quenched into 4 N HCl. The resulting layers were separated and the aqueous layer was extracted with Et2O (3×250 mL). The combined organic extracts were washed with H2O (3×150 mL), saturated NaHCO3 (3×150 mL), brine (1×150 mL), dried over MgSO4 and concentrated. The concentrate was added to a slurry of AlCl3 (9.0 g, 10 eq) and NaCl (2.4 g, 6 eq) at 130 C. The resulting mixture was stirred at 180 C. for 2 hours. Alternatively, this concentrate was mixed with concentrated sulfuric acid and the resulting mixture was stirred at 85 C. one hour. The reaction mixture was cooled to room temperature and ice was slowly added, followed by concentrated HCl. The resulting mixture was extracted with CH2Cl2 (3×500 mL) and the combined organic extracts were concentrated and purified by column chromatography using hexane:EtOAc (4:1) as eluant to give the desired substituted indanonesxix. Thus, the title fluoroethyl ureas were obtained from these indanones according the protocol described in general procedure C.Synthesis of 1-(2-fluoro-ethyl)-3-(7-fluoro-indan-1-yl)-ureaThe title compound was generated from commercially available 2-fluororobenzoic acid according to the general procedure E described above. The intermediates 7-fluoro-1-indanone and 7-fluoro-indan-1-ylamine were isolated and characterized.7-Fluoro-1-indanone: 6.85 g (32%) of the title indanone was obtained from 2-fluoro-benzoic acid (20.00 g, 0.14 mol), SOCl2(15.60 mL, 0.21 mol), AlCl3 (19.00 g, 0.14 mol), an additional AlCl3 (285.50 g, 2.14 mol) and NaCl (75.10 g, 1.29 mol) according to the protocols as outlined in general procedure E above. Spectroscopic data: 1H NMR (300 MHz, CDCl3) delta 2.67-2.80 (m, 2H), 3.2 (t, 2H, J=5.9 Hz), 7.0 (t, 1H, J=8.5 Hz), 7.3 (d, 1H, J=7.6 Hz), 7.6 (m, 1H).
General procedure: At firstseveral different acyl hydrazines Bwere synthesized. To do this, we have started with corresponding carboxylicacid A in solvent EtOH (2 mL/mmol), 4 equivalents ofthionyl chloride (SOCl2) was added dropwise at room temperature andrefluxed with stirring for 5-12 h (monitored by TLC). SOCl2 and EtOHwas evaporated. Water was added to the crude mixture, extracted withdichloromethane (DCM) and dried with anhydrous Na2SO4.Solvent DCM was evaporated and the residue was dried at high vacuum whichprovided the ethyl ester of the corresponding carboxylic acid A.The ester was added dropwise to hydrazinehydrate (NH2NH2,H2O) (5mmol/1mmol of ethylcarboxylate) and heated at 80 C for 5-20 hours (monitored by TLC) and allowedto stand for 12 hours. If solid appeared it was filtered and the residue wasdissolved in DCM and dried with anhydrous Na2SO4, DCM wasthen evaporated and the solid was dried at high vacuum. If solid was notobserved then the reaction mixture was extracted several occasions by DCM, andthe combined organic layer was dried with anhydrous Na2SO4. DCM was evaporated and residue was dried at high vacuum that leads usdifferent acyl hydrazine Bcorresponding to the starting carboxylic acid A.
With sulfuric acid; In water; for 6h;Reflux;
General procedure: Hydrazides (30-58) were synthesized by one pot conventionalmethod24 Benzoic acid or its derivative (10 mmol) was dissolvedin ethanol (20 mL). Sulfuric acid (3 N, 2 mL) was added and thereaction contents were refluxed for six hours. The reaction wasmonitored with TLC. After the completion of the reaction, the reactionmixture was neutralized by adding solid NaHCO3, and filteredto remove excess of NaHCO3. In the neutralized reaction mixture which contains ethyl ester, hydrazine monohydrate (1.5 mL,3 mmol) was added and refluxed for 3-6 h to complete the reaction.Ethanol and unreacted hydrazine were removed by distillationupto 1/3 volume. The reaction contents were cooled, filteredand recrystallized from methanol to obtain the desired hydrazidecrystals (see Supporting information).
With sulfuric acid; for 8h;Reflux;
General procedure: To a solution of substituted benzoic acid (1-15)(0.246 mol) in dry ethanol (2.5 mol), concentrated sulphuricacid (0.5 mL) was added. The reaction mixture was refluxedfor 8 h. Excess of ethanol was distilled off and the contentwas allowed to cool. The residue was poured into separatingfunnel containing 60 mL of water. Carbon-tetrachloride(5-10 mL) was added to obtain sharp separation of aqueousand ester layer. Ester layer was washed with sodiumhydrogen carbonate solution. The esters (16-30) were collected and recrystallized from ethanol. Details of thesecompounds are available in Supplementary Information.
4.9 g
With sulfuric acid;Reflux;
O-fluorobenzoic acid (5g, 35.7mmol) was dissolved in 20mL of ethanol, a catalytic amount of concentrated sulfuric acid was added dropwise, and the mixture was stirred at reflux overnight. After the reaction was completed, the ethanol was rotated.Extracted with ethyl acetate (25 mL × 3),The organic phase is combined, washed with saturated sodium hydrogen carbonate solution, washed with saturated brine and dried over anhydrous sodium sulfate.Concentrated to give a colorless oily productEthyl fluorobenzoate 4.9g;Ethyl fluorobenzoate (4.9 g, 29.1 mmol) was dissolved in 20 mL of DMSO, and morpholine (12.7 mL, 145.7 mmol) was added dropwise and stirred at 120 overnight.After the reaction, ethyl acetate was extracted (25 mL×3), and the organic phase was combined, washed with water (25 mL×3),After concentration, the oily product was 4.5 g;The above product (4.5 g, 19.1 mmol) was dissolved in 10 mL of methanol.Add 10 mL of 10% aqueous NaOH solution.After stirring at 80 C for 2 h, the methanol was rotated, and the pH was adjusted to 4 with 10% dilute hydrochloric acid.Solid precipitated and filtered to obtain 3.2 g of 2-morpholinylbenzoic acid.Three-step yield of 43.2%;The o-fluorobenzoic acid (50 mg, 0.24 mmol) was obtained in the same manner as in Example 1 to obtain 45g, two-step yield 54.9% of the product.
EXAMPLE-13: Synthesis of 4-amino-5-fluoro-1-(2 ?-hydroxymethyl-[1,3]-oxothiolane- 5S-yl)1tf-pyrimidin-3-one. 2-fluorobenzoic acid salt (formula-8b1); Dipotassium hydrogen orthophosphate (83.3 g) was dissolved in a mixture of industrially methylated spirit (IMS, 600 mL) & purified water (200 mL) and the obtained solution was cooled to 18C. The compound of formula-7b (100 g, 0.26 mol) was added at 15-22C and the suspension was stirred at 18-22C for 1 h. A solution of sodium borohydride (20. 4 g (0.54 mol) in water (110 mL) containing sodium hydroxide (40 mg)) was added drop wise by keeping temperature at 18-22C and maintained for 4 h. The completion of the reaction was confirmed by TLC. The reaction mass was transferred into a separating funnel and the layers were separated. The organic layer pH was adjusted to 5.9-6.3 with aq. HCI (~25 mL) and readjusted to pH 7.5-7.8 with sodium hydroxide (15 mL, 15% w/w) and filtered. IMS (~790 mL) was distilled out initially atmospherically followed by reduced pressure to reduce the traces of IMS. The resultant residue was diluted with water (200 mL) and then cooled to 22-30C. Toluene (150 mL) was added to the reaction mass under stirring, allowed the layers to settle and separate the layers. Toluene layer was washed with water (100 mL) and combined aqueous layer was charcoalized. The filtrate was warmed to 38-42C, 2- fluorobenzoic acid (37 g, 0.26 mol) was added and stirred for 2h at the same temperature. The reaction mass was cooled to 22-30C and maintained for 3-4h. The separated solid was filtered and washed with pre-cooled water and dried to get compound of formula-8b. in 80 g. 1H NMR (300 MHz, DMSO-d6): delta 13.40 (brs, 1H), 8.20 (d, 1 H, J=7.2 Hz), 7.84-8.00 (m, 2H), 7.58-7.68 (m, 2H), 7.28-7.34 (m, 2H), 6.12-6.16 (m, 1H), 5.41 (t, 1 H, J=5.4 Hz), 5.18-5.20 (t, 1 H, J=3.9 Hz), 3.70 -3.82 (m, 2H), 3.39-3.45 (m, 1H), 3.09-3.15 (dd, 1 H, J=11.85 & 4.35 Hz).
General procedure: Equimolar quantities of compound 2 (1 mmol) and a substituted carboxylic acid were dissolved in phosphoryl chloride (5 mL) and heated at 80C for 3-6 h, the progress of reaction being monitored by TLC. The reaction mixture was then heated under reduced pressure to allow excess phosphoryl chloride to distill off, and the residue was subjected to flash chromatography on silica gel using 15-25% acetone in petroleum ether as eluent to give the target compounds 3a-m (Table 1).
To a pressure vessel containing <strong>[3537-14-2]5-nitropyridine-2,3-diamine</strong> 106 (125 mg, 0.8 mmol) and 2-fluorobenzoic acid 107 (1 12.17 mg, 0.8 mmol) was added Eaton's reagent (2 ml, 12.73 mmol). The reaction mixture was stirred at 150 C. The mixture was cooled to room temperature and quenched with water. The precipitate was collected and dried under vacuum to provide compound 108. The compound was used for subsequent reaction without purification.
2-[(2-fluorobenzoyl)amino]-4-(pyridin-2-yl)thiazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
58%
General procedure: 5.1.3. General procedure C. To the carboxylic acid substrate (0.42 mmol, 1.2 equiv) in DMF (1.5 mL) was added CDI (0.50 mmol, 1.1equiv) and DBU (0.67 mmol, 1.9 equiv). The reaction was stirred for 30 min at 23 C. Next, 2-amino-4-(2-pyridyl)thiazole 20 (0.35 mmol, 1.0 equiv) was added and the reaction mixture was stirred for 16 h at 23 C. A small amount of silica gel was added to the reaction mixture, which was concentrated in vacuo under reduced pressure. The crude product impregnated on the silica gel was purified by silica gel flash chromatography (0-10% MeOH-CH2Cl2) to afford the title compound.
General procedure: Compounds 6a-t were synthesized from substituted benzoic acid via six steps according to the literature method as described. Various substituted benzoic acids 1a-t were treated with SOCl2 to give compounds 2a-t, which were reacted with CH3OH and EtN3 in CH2Cl2 at 0 to afford compounds 3a-t. Compounds 4a-t were prepared by the reaction of compounds 3a-t, hydrazine hydrate in CH3OH under reflux condition about 5h. Subsequently, compounds 5a-t were obtained by reaction of compounds 4a-t with CS2 and KOH in CH3OH. Compounds 6a-t were obtained by the cyclization reaction of compounds 5a-t in the presence of HCl at 0-5°C.
6-bromo-2-(3-fluorophenyl)-1-methyl-1H-benzo[d]imidazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
2-Fluorobenzoic acid (128 mg, 0.91 mmol) and carbonyl diimidazole (170 mg, 1.05 mmol) were dissolved in butyronitrile (3 mL). After stirring at room temperature for 15 minutes, Example 271B (183 mg, 0.91 mmol) was added. The reaction mixture was heated at 180 C. for 30 minutes in a Biotage Initiator microwave reactor. The reaction mixture was concentrated and acetic acid (2 mL) was added. After heating at 150 C. for 20 minutes, the residue was partitioned between 50 mL of ethyl acetate and 50 mL of water. The aqueous layer was removed and the organic layer was washed with aqueous saturated sodium bicarbonate (30 mL), dried over sodium sulfate, filtered and concentrated. Purification by silica gel flash chromatography eluting with 20% ethyl acetate in hexanes gave the title compound. MS (DCI) m/e 305.0 (M+H)+
With tert.-butylhydroperoxide; Ru[2-(2-pyridymethylimino)ethylbenzimidazole]pyridinedicarboxylate; In neat (no solvent); at 40℃; for 7.5h;
General procedure: In a typical process, into a 5ml two-necked, round-bottom flask equipped with a magnetic stirrer and a thermometer were added the ruthenium complex [Ru(pymieb)(pydic)] (0.002mmol) and the substrate alcohol (2mmol) successively. The mixture was heated to 40C under stirring. Then t-butyl hydroperoxide (TBHP) was added dropwise to the mixture and the temperature was kept at 40C until completion of the reaction. The reaction samples were analyzed on a Shandong Lunan Ruihong Gas Chromatograph (SP-6800A) equipped with a FID detector and a SE 30 column (30m×0.5mm). The conditions used in gas chromatography were temperature of the detector 280C, column temperature 130-220C (varying with alcohols), pressure of the carrier gas 0.05-0.07MPa (varying with alcohols).
General procedure: Under an argon atmosphere, liquid NH3 (25 mL) was condensedin a two-neck round-bottom flask immersed in a dry ice coolingbath and equipped with a dry ice reflux condenser. Aldehyde(7.34 mmol) was added, and the resulting solution (or suspension)was stirred for 1 h. KMnO4 (7.34 mmol, 1.16 g) was added,the cooling bath was removed, and the reaction mixture wasstirred for another hour with gentle reflux of NH3. Na2SO3 (22.0mmol, 2.78 g) was added, the reflux condenser was removed,and the NH3 was allowed to evaporate spontaneously. The darkbrownresidue was treated with 6 M HCl (30 mL), and theresulting precipitate was filtered, washed with H2O (100 mL)and sat. aq NaHCO3 (20 mL). All products were recrystallizedfrom EtOH.
24%
General procedure: Under an argon atmosphere, liquid NH3 (25 mL) was condensedin a two-neck round-bottom flask immersed in a dry ice coolingbath and equipped with a dry ice reflux condenser. Aldehyde (7.34 mmol) was added, and the resulting solution (or suspension)was stirred for 1 h. KMnO4 (7.34 mmol, 1.16 g) was added,the cooling bath was removed, and the reaction mixture wasstirred for another hour with gentle reflux of NH3. Na2SO3 (22.0mmol, 2.78 g) was added, the reflux condenser was removed,and the NH3 was allowed to evaporate spontaneously. The darkbrownresidue was treated with 6 M HCl (30 mL), and theresulting precipitate was filtered, washed with H2O (100 mL)and sat. aq NaHCO3 (20 mL). All products were recrystallizedfrom EtOH.
5.1.5 Preparation of 1-(2-fluorobenzoyl)piperazine (5) A solution of 2-fluorobenzoic acid (7.00 g, 0.05 mol) and CDI (8.90 g, 0.055 mol) was stirred in dry THF (30 mL) at room temperature for 30 min. In a separate round bottom flask add piperazine (10.76 g, 125 mmol) and <strong>[142-64-3]piperazine dihydrochloride</strong> (20.0 g, 125 mmol) in 60 mL of water. Stir the reaction mixture for 5 min and add 14.0 g of NaCl. Add this brine solution to the round bottom flask containing acyl imidazole. Stir the reaction mixture for 5 hour. The mixture was filtered and the filtrate distilled by rotary evaporation to remove THF. The aqueous layer was washed with ethyl acetate (3 * 10 mL) to remove diacylated product. The PH of the aqueous layer was adjusted to about 9 using saturated solution of NaOH and washed with ethyl acetate (4 * 30 mL). The aqueous layer was discarded. The organic layer was washed with water (4 * 25 mL), dried over anhydrous Na2SO4 and concentrated by rotary evaporation and purified by flash chromatography to afford 1-(2-fluorobenzoyl)piperazine as colourless solid (4.90 g, 48%). The other intermediates 1-(2-chlorobenzoyl)piperazine (6) and 1-[3-(trifluoromethyl)benzoyl]piperazine (7) were prepared by using the general procedure described above.
With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; for 2h;
2-Fluoro-N-methoxy-N-methylbenzamide was prepared in 73% yield according to the Example 1 , Step A substituting 6-bromopicolinic acid for 2-fluorobenzoic acid.
The synthesis of 2-fluoro-6-trimethylsilylbenzoic acid (7) under EQ conditions (Table 1, entry 2) is described as follows. n-BuLi (1.6M in hexane, 26 mL, 41 mmol) was added dropwise to a solution of <strong>[2252-37-1]2-fluoro-6-bromobenzoic acid</strong> (10) (4.38 g, 20 mmol) in dry THF (120 mL) at -90 C. The mixture was stirred for 2 h, and TMSCl (9.2 mL, 70 mmol) was added. The solution was hydrolyzed with 1M NaOH (pH 10-11), and the aqueous layer was washed with ether (250 mL) and acidified with 2M HCl (pH 1-2). After extraction of the aqueous layer with ether (360 mL), the combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum to give a sticky residue containing 2-fluoro-6-trimethylsilylbenzoicacid (7) (82% yield) and 2-fluorobenzoic acid (10% yield) (the yields were estimated by 1H NMR analysis). 2-Fluoro-6-trimethylsilylbenzoic acid (7) was separated by chromatography on silica gel (hexane/ether 90 : 10) as a whitesolid (2.0 g, 47 %), mp 88.4-898C. nmax (neat)/cm1 2957, 2654,1686, 1464, 1291, 1236. dH (CDCl3, 400 MHz) 7.47-7.52 (2H,m), 7.14 (1H, m), 0.34 (9H, s). dC (CDCl3, 50 MHz) 172.8, 161.0(d, J 258.0), 144.1, 132.6 (d, J 8.1), 130.6, 124.1 (d, J 10.6),117.0 (d, J 22.3), 0.54.
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃;
General procedure: Compound 13 (72 mg, 0.2 mmol) was synthesized from 1 by oxidation with Jones Reagent andno further purification was needed for the next step [14]. Compound 1 or 13 (72 mg, 0.2 mmol) wasdissolved in 10 mL of dichloromethane and mixed with corresponding acid (0.24 mmol), EDCI andDMAP. The reaction was stirred at room temperature and monitored by TLC. After 6-8 h, the mixturewas poured into 10 mL of 10% HCl, and then extracted with DCM three times (each 10 mL). The organiclayer was combined, washed with water and saturated brine, sequentially, then dried over anhydrousNa2SO4, and concentrated in vacuo. The crude product was purified by column chromatography(MeOH/DCM 1:150 v/v) to give the target compounds 2-12 and 14-24.
The catalyst dissolved in fresh o-fluorotoluene added to the primary oxidation reactor is a mixture of metal phthalocyanine with the structure of formula (IV) (R1=H, R2=CH3CH2, M=Co) and manganese acetylacetonate in a total concentration of 450 ppm . The flow rate of fresh o-fluorotoluene in the oxidation reactor was 10.9mL / h, and the average residence time of the oxidation reactor in liquid phase was 2.2h. Continuously into the oxidation reactor, maintaining the system reaction temperature of 185 C, the reaction pressure of 1.7MPa. The volume ratio of water added into the hydrolysis reactor to the oxidation reaction volume of the hydrolysis reactor was 0.90: 1, the reaction temperature in the hydrolysis reactor was maintained at 144 C and the reaction pressure was 1.2 MPa. The retention time of liquid phase was 1.6 h. The liquid phase at the outlet of the hydrolysis reactor was continuously fed into a liquid-liquid delaminator at a temperature of 108 C and a pressure of 1. IMPa. The conversion of o-fluorotoluene was 97.0%. The selectivities of o-fluorobenzyl alcohol, o-fluorobenzaldehyde and o-fluorobenzoic acid were 60.0%, 30.7% and 9.3%, respectively. Other byproducts were not detected.
tert-butyl 2-(2-fluorobenzoyl)-2,8-diazaspiro[4.5]decane-8-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
With N-ethyl-N,N-diisopropylamine; HATU; In acetonitrile; at 25℃; for 16h;
To a suspension of te/ -butyl 2,8-diazaspiro[4.5]decane-8-carboxylate (200 mg, 0.832 mmol) in acetonitrile (2 mL) were added 2-fluorobenzoic acid (175 mg, 1.25 mmol), 0-(7- azabenzotriazol-1-yl)-/V,//,A/',//-tetramethyluronium hexafluorophosphate (HATU; 506 mg, 1.33 mmol), and /V,/V-diisopropylethylamine (323 mg, 2.50 mmol). The reaction mixture was stirred at 25 C for 16 hours, whereupon it was concentrated in vacuo. The residue was dissolved in methanol (8 mL), treated with ion exchange resin Amberlyst A26, hydroxide form [3.6 g, pre- washed with methanol (7 mL)], stirred at 25 C for 1 hour, and filtered. The filtrate was concentrated under reduced pressure and subjected to silica gel chromatography (Gradient: 0% to 50% ethyl acetate in petroleum ether), affording the product as a colorless gum. By 1 H NMR analysis, this was judged to be a mixture of rotamers. Yield: 231 mg, 0.637 mmol, 77%. 1 H NMR (400 MHz, CD3OD) delta 7.55-7.46 (m, 1 H), 7.45-7.38 (m, 1 H), 7.32-7.26 (m, 1 H), 7.26-7.18 (m, 1 H), 3.72-3.66 (m, 1 H), 3.56-3.47 (m, 1 H), 3.51 (s, 1 H), 3.46-3.3 (m, 4H), 3.21 (br s, 1 H), [1.94 (dd, J=7.5, 7.3 Hz) and 1.87 (dd, J=7.3, 7.0 Hz), total 2H], 1.66-1.48 (m, 4H), [1.47 (s) and 1.43 (s), total 9H].
With picoline; tert.-butylhydroperoxide; chlorophyllin coppered trisodium salt; In water; at 80℃; for 15h;
General procedure: A solution of benzyl alcohol (1 mmol), SCC (1 mol %), 70% TBHP (1 mmol or 3 mmol),and 4-methylpyridine (1.0 mmol) in H2O (2 mL) was stirred at 60 C (or 80 C) for 10 h (or 15 h).The reaction mixture was quenched with a saturated solution of sodium thiosulfate (5 mL) andextracted using dichloromethane (3 10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtrated, and then the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel with petroleum ether/ethyl acetate as the eluent to obtain the desired product.
With oxygen; 1-hydrosilatrane; sodium hydroxide; In N,N-dimethyl-formamide; at 20℃; for 0.5h;
General procedure: To a 2 dram vial containing a stir bar was added silatrane (0.15 mmol), aldehyde (0.1 mmol), and DMF (1 mL). The solution was stirred for 5 min to allow for all the silatrane to dissolve, after which additive (1 pellet of NaOH finely ground) was added. After 30 min of stirring in ambient conditions the solution was washed once with 1 M HCl, then extracted three times with dichloromethane and once with diethyl ether. The resulting organic extract was concentrated under reduced pressure and used to determine yield without any further purification. All of the alcohols synthesized are known compounds.
74
[ 199447-10-4 ]
[ 445-29-4 ]
[ 775304-57-9 ]
Yield
Reaction Conditions
Operation in experiment
65%
With tetrachloromethane; diethoxymethylsilane; Bis(p-nitrophenyl) phosphate; triphenylphosphine; In toluene; at 120℃; for 24h;Reflux; Large scale;
To the reactor was added o-fluorobenzoic acid (4,140 g, 1 mol), compound 3 (180 g, 1 mol), triphenylphosphine(52.4 g, 0.2 mol) carbon tetrachloride (152 g, 1 mol), diethoxymethylsilane (202.6 g, 1.2 mol)Bis (p-nitrophenyl) phosphate (17.1 g, 0.05 mol),500mL of toluene. 120 oil bath heated to reflux condensation reaction for 24 hours. Until the reaction liquid coldAfter that, it was extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by column chromatography to give the title compoundAtaluren (1,184.6 g) as a white solid in 65% yield
With bis-triphenylphosphine-palladium(II) chloride; 1,10-Phenanthroline; copper (I) acetate; sodium hydroxide; In dimethyl sulfoxide; at 140℃; for 5h;Inert atmosphere;
Dimethyl sulfoxide (200 mL) was added to a 500 mL three-neck flask, and 2-fluorobenzoic acid (II) (14.2 g, 0.1 mol) was added under nitrogen.5-bromopyrrole-3-carbaldehyde (III) (35.5 g, 0.2 mol), sodium hydroxide (40.1 g, 1 mol), Pd(PPh3)2Cl2 (14.1 g, 0.02 mol), CuOAc (4.9 g, 0.04 mol) ,1,10-Phenanthroline (7.3g, 0.04mol), stirring, heating to 140C, reaction for 5h,The reaction was completed by HPLC (2-fluorobenzoic acid (II) content is less than 1%), the temperature was lowered to 20C, the pH was adjusted to 6 with 5% aqueous hydrochloric acid solution, and the solid was slowly precipitated by adding water.The solid was extracted with ethyl acetate (50 mL X 3).The resulting organic phase was washed with saturated sodium bicarbonate solution (100 mL) and saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to 80 g and re-crystallized by the dropwise addition of petroleum ether (150 mL).Filtration drying gave a reddish solid product (18.5 g, yield: 96.5% based on 2-fluorobenzoic acid (II)).
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 3h;
General procedure: A mixture of a carboxylic acid (2 mmol), the corresponding amidine salt (2 mmol), HBTU (834 mg, 2.2 mmol) and DIPEA (1.03 g,8 mmol) in DMF (8 mL) was stirred at room temperature for 3 h. Itwas then quenched with H2O (30 mL) and extracted with EtOAc(3 10 mL). The combined organic layer was washed with H2O(10 mL) and brine (10 mL) successively, dried over anhydrous Na2SO4, concentrated, and purified through silica gel column chromatography to give the substrate 2.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl acetamide;
General procedure: To a solution of corresponding acids (RCOOH, 0.63 mmol), HOBt (170 mg, 1.26 mmol), EDCI (242 mg, 1.26 mmol), and DIPEA (0.208 mL, 1.26 mmol) were added to DMA (60 mL), and then 4 (186 mg, 1.26mmol) were added, the mixture was stirred overnight. The mixture was dissolved in water, then the aqueous solution was extracted with ethyl acetate (50 mL 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated to give the crude product, which was purified by column chromatography to give N-(4-nitrophenethyl)amide (5) in a good yield. And to a solution of 5 in MeOH was added 10% Pd/C under H2 at reflux overnight, then the mixture was dissolved in water, then the aqueous solution was extracted with ethyl acetate (50 mL 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated to give the crude product, which was purified by column chromatography to give N-(4-aminophenethyl)amide (6) in a good yield. Then the mixture of 3 and 6 was added NaCNBH3 in MeOH and the solution was stirred under reflux overnight. After reaction completed, the solvent was removed under reduced pressure and the residue was dissolved in water, the aqueous solution was extracted with ethyl acetate (50 mL 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated to give the crude product, which was purified by column chromatography to afford the corresponding compounds (7-26) in good yields.
General procedure: Complex 1 was prepared by the reaction of an aqueous solution of copper(II) acetate monohydrate (1mmol, 0.20g) with N-methylnicotinamide (2mmol, 0.27g) followed by addition of 4-fluorobenzoic acid (2mmol, 0.28g). The reaction mixture was stirred until a blue product was precipitated (3days). The fine blue microcrystals were filtered off, washed with a small portion of water and dried at ambient temperature. The mother liquor obtained from filtration were left to crystallize. The blue crystals suitable for X-ray structure determination were separated after several days. Yield: 0.41g (65%).
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